For the past 20 years, we have studied the genetic underpinnings of hormonal factors leading to hypertension (HTN) in the HyperPATH cohort. From these studies, we have identified several associations between single nucleotide polymorphic (SNP) markers on candidate genes and specific intermediate phenotypes of the HTN. This proposal will focus on one of these identified phenotype/genotype associations. The intermediate phenotype is derived from the aldosterone (ALDO) response to angiotensin II (ANGII) on a sodium-restricted intake. This phenotype is heritable in the hypertensive population, is bimodally distributed in the hypertensive but not normotensive population and the hypertensive intermediate phenotype consists of those subjects in the lower mode that comprise 25% of hypertensives and <2% of normotensives. Associated with this subset is an enhanced sodium sensitivity of blood pressure and a defect in the vasculature, specifically the renovasculature. The genetic mechanisms responsible for these effects are unclear. One candidate is the recently described, first identified, histone demethylase that is linked to and whose action is modified by steroids---lysine-specific demethylase 1 (LSD1). A positive association between SNPs in LSD1 and ALDO response to ANGII was only observed in hypertensives and not normotensives. We then extended our studies in two ways: assessing LSD1 SNPs relationship to other phenotypic characteristics in humans (the minor allele also was associated with low urine ALDO levels on a high salt diet and sodium sensitivity of BP) and studying in experimental animals the relationship between LSD1, ALDO, the mineralocorticoid receptor (MR), and vascular injury. Our preliminary data suggest that LSD1: is present in vascular and cardiac tissue;is regulated by NA intake;is decreased by ALDO with the reversal by administering an MR antagonist;and is reduced in a CV injury model with parallel increases in its level and reduction in CV damage with MR blockade. The overall goal of the present proposal is to expand on these preliminary findings by characterizing the mechanisms underlying the interactions between LSD1, ALDO and the vasculature and their involvement in the pathophysiology of cardiovascular disease. Three approaches will be used. 1) We will assess phenotypic associations to polymorphism in the LSD1 gene to other genes and in the HyperPATH cohort and in a different cohort. 2) We will define LSD1's role in ALDO secretion. 3) We will extend our mechanistic studies of LSD1 from the adrenal to the vasculature. Thus, these positive results have formed the basis of the present proposal: a translational research project based on preliminary results from both the bench and the clinical research center. We will use in vivo and in vitro studies on vessels and adrenals in both humans (from our HyperPATH cohort) and animals (the LSD1 heterozygote knockout mouse where the LSD1 levels are 50% of that in the wild type). Vascular reactivity of vessels, molecular biologic and cell biologic techniques will be used. PUBLIC HEALTH RELEVANCE: Aldosterone is a hormone secreted by the adrenal gland whose function traditionally has been assumed to be to modify the kidney's ability to excrete potassium and sodium. However, recently aldosterone also has been implicated in having a major, adverse impact on the vasculature and by extension cardiovascular disease by uncertain mechanisms. This project is designed to assess one of those mechanisms thereby providing entrie to developing more directed therapy to treat cardiovascular diseases.